Intermittent stress augmentation pacing for cardioprotective effect

ABSTRACT

A device and method for delivering electrical stimulation to the heart in a manner which provides a protective effect is disclosed. The protective effect is produced by configuring a cardiac pacing device to intermittently switch from a normal operating mode to a stress augmentation mode in which the spatial pattern of lo depolarization is varied to thereby subject a particular region or regions of the ventricular myocardium to increased mechanical stress.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/458,286, filed Jul. 18, 2006, which is a continuation-in-part of U.S.patent application Ser. No. 11/030,575 filed Jan. 6, 2005, now issued asU.S. Pat. No. 7,295,874, which are hereby incorporated by reference.

FIELD OF THE INVENTION

This invention pertains to apparatus and methods for the treatment ofheart disease and to devices providing electrostimulation to the heartsuch as cardiac pacemakers.

BACKGROUND

Coronary artery disease (CAD) occurs when the coronary arteries thatsupply blood to the heart muscle become hardened and narrowed due toatherosclerosis. The arteries harden and become narrow due to thebuildup of plaque on the inner walls or lining of the arteries. Bloodflow to the heart is reduced as plaque narrows the coronary arteries.This decreases the oxygen supply to the heart muscle. CAD is the mostcommon type of heart disease, which is the leading cause of death in theU.S. in both men and women.

An atherosclerotic plaque is the site of an inflammatory reaction withinthe wall of an artery and is made up of a core containing lipid andinflammatory cells surrounded by a connective tissue capsule. Amyocardial infarction (MI), or heart attack, occurs when atheroscleroticplaque within a coronary artery ruptures and leads to the clotting ofblood (thrombosis) within the artery by exposing the highly thrombogeniclipid core of the plaque to the blood. The complete or nearly completeobstruction to coronary blood flow can damage a substantial area ofheart tissue and cause sudden death, usually due to an abnormal heartrhythm that prevents effective pumping.

Besides causing an MI, CAD can also produce lesser degrees of cardiacischemia due to the narrowing of a coronary artery lumen byatherosclerotic plaque. When blood flow and oxygen supply to the heartis reduced, patients often experience chest pain or discomfort, referredto as angina pectoris. Angina pectoris serves as a useful warning ofinsufficient myocardial perfusion which can lead to the more serioussituation such as a heart attack or cardiac arrhythmia. Patients whoexperience anginal episodes are commonly treated either with medicationor by surgical revascularization. It has also been found, however, thatpatients who experience anginal episodes prior to a heart attack oftenhave a lower mortality rate than heart attack patients who do notexperience such episodes. It is theorized that this phenomenon may bedue to ischemic preconditioning of the heart by the anginal episodeswhich thereby renders the myocardial tissue less likely to becomeinfarcted if blood supply is sharply reduced by a subsequent coronarythrombus.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an exemplary cardiac rhythm managementdevice for practicing the present invention.

FIG. 2 illustrates an exemplary algorithm for implementing intermittentstress augmentation pacing.

FIG. 3 illustrates ischemic changes in a recorded electrogram.

DETAILED DESCRIPTION

The present disclosure relates to a method and device which employspacing therapy to precondition the heart to be less vulnerable to suddenreductions in blood flow. It has been found that intermittent pacing ofthe heart results in a cardioprotective effect which renders themyocardium more resistant (i.e., less likely to become infarcted) duringa subsequent episode of myocardial ischemia. As explained below, pacingtherapy may be applied in such a manner that certain regions of theventricular myocardium are subjected to an increased mechanical stress.It is believed that the increased myocardial stress preconditions theheart to better withstand the effects of subsequent ischemia through asignal transduction cascade which causes the release of certain cellularconstituents and/or induces expression of particular genes. Themechanism responsible for the cardioprotective effect of increasedstress may or may not be similar to the mechanism by which priorischemia preconditions the heart. It has been experimentally observed inanimal studies, however, that pacing therapy causing increased stress toa particular region of the myocardium can produce a cardioprotectiveeffect without making the region ischemic.

Described below is an exemplary device for delivering pacing therapy ina manner which preconditions the heart to better withstand subsequentischemia, referred to herein as intermittent stress augmentation pacing.Also set forth is an explanation as to how pacing may produce increasedmechanical stress to a myocardial region and an exemplary pacingalgorithm.

1. Mechanical effects of pacing therapy

The degree of tension or stress on a heart muscle fiber as it contractsis termed the afterload. Because pressure within the ventricles risesrapidly from a diastolic to a systolic value as blood is pumped out intothe aorta and pulmonary arteries, the part of the ventricle that firstcontracts does so against a lower afterload than does a part of theventricle contracting later. The degree to which a heart muscle fiber isstretched before it contracts is termed the preload. The maximum tensionand velocity of shortening of a muscle fiber increases with increasingpreload, and the increase in contractile response of the heart withincreasing preload is known as the Frank-Starling principle. When amyocardial region contracts late relative to other regions, the earliercontraction of opposing regions stretches the later contracting regionand increases its preload. Thus, a myocardial region which contractslater than other regions during systole is subjected to both anincreased preload and an increased afterload, both of which cause theregion to experience increased wall stress.

When the ventricles are stimulated to contract by a pacing pulse appliedthrough an electrode located at a particular pacing site, the excitationspreads from the pacing site by conduction through the myocardium. Thisis different from the normal physiological situation, where the spreadof excitation to the ventricles from the AV node makes use of theheart's specialized conduction system made up of Purkinje fibers whichallows a rapid and synchronous excitation of the entire ventricularmyocardium. The excitation resulting from a pacing pulse applied to asingle site, on the other hand, produces a relatively asynchronouscontraction owing to the slower velocity at which excitation isconducted through the myocardium. Regions of the myocardium located moredistally from the pacing site are excited later than regions proximal tothe pacing site and, for the reasons explained above, subjected toincreased mechanical stress.

The ventricular contractions resulting from pacing pulses are thusgenerally not as synchronized as intrinsic contractions and maytherefore be hemodynamically less efficient. For example, inconventional bradycardia pacing, the pacing site is located in the rightventricle so that excitation must spread from the right ventricularpacing site through the rest the myocardium. The left ventricularcontraction then occurs in a less coordinated fashion than in the normalphysiological situation which can reduce cardiac output. This problemcan be overcome by pacing the left ventricle, either in addition to orinstead of the right ventricle, to produce a more coordinatedventricular contraction, referred to as cardiac resynchronizationpacing. Resynchronization pacing, besides overcoming the desynchronizingeffects of conventional pacing therapy, may also be applied to patientswho suffer from intrinsic ventricular conduction deficits in order toimprove the efficiency of ventricular contractions and increase cardiacoutput. Ventricular resynchronization therapy may be delivered as leftventricle-only pacing, biventricular pacing, or pacing delivered tomultiple sites in either or both ventricles.

In contradistinction to resynchronization therapy, pacing therapydelivered to produce a cardioprotective effect is pacing which isintended to produce a relatively asynchronous contraction so thatmyocardial regions located more distally from the pacing site aresubjected to increased mechanical stress. Such pacing, referred to asstress augmentation pacing, produces a pattern of myocardialdepolarization which is different from the dominant or chronicdepolarization pattern resulting from intrinsic or paced activation. Ifstress augmentation pacing is delivered on a relatively constant basis,however, the later contracting ventricular regions can undergohypertrophy and other remodeling processes in response to the increasedstress, and such remodeling can counteract the cardioprotective effects.The effectiveness of stress augmentation pacing is therefore increasedif such pacing is delivered as a single treatment or multiple treatmentsspread over some period of time so that remodeling does not occur.Stress augmentation pacing may be delivered by a variety of means. Inone embodiment, an external pacing device delivers pacing pulses to theheart via pacing electrodes which are incorporated into a catheter whichmay be disposed near the heart. Such a catheter may be one which is alsoused for other types of cardiac treatment or diagnosis such asangiography or angioplasty. Stress augmentation pacing may also bedelivered by an implantable pacing device. As described below, a cardiacpacing device may be programmed to deliver pacing which stresses aparticular myocardial region on an intermittent basis. The device mayalso be configured to intermittently pace multiple pacing sites in orderto provide a cardioprotective effect to multiple myocardial regions.

2. Exemplary Cardiac Device

Cardiac rhythm management devices such as pacemakers are usuallyimplanted subcutaneously on a patient's chest and have leads threadedintravenously into the heart to connect the device to electrodes usedfor sensing and pacing. A programmable electronic controller causes thepacing pulses to be output in response to lapsed time intervals andsensed electrical activity (i.e., intrinsic heart beats not as a resultof a pacing pulse). Pacemakers sense intrinsic cardiac electricalactivity by means of internal electrodes disposed near the chamber to besensed. A depolarization wave associated with an intrinsic contractionof the atria or ventricles that is detected by the pacemaker is referredto as an atrial sense or ventricular sense, respectively. In order tocause such a contraction in the absence of an intrinsic beat, a pacingpulse (either an atrial pace or a ventricular pace) with energy above acertain pacing threshold is delivered to the chamber.

FIG. 1 shows a system diagram of a microprocessor-based cardiac rhythmmanagement device or pacemaker suitable for practicing the presentinvention. The controller of the pacemaker is a microprocessor 10 whichcommunicates with a memory 12 via a bidirectional data bus. The memory12 typically comprises a ROM (read-only memory) for program storage anda RAM (random-access memory) for data storage. The controller could beimplemented by other types of logic circuitry (e.g., discrete componentsor programmable logic arrays) using a state machine type of design, buta microprocessor-based system is preferable. As used herein, the term“circuitry” should be taken to refer to either discrete logic circuitryor to the programming of a microprocessor.

The device is equipped with multiple electrodes each of which may beincorporated into a pacing and/or sensing channel. Shown in the figureare four exemplary sensing and pacing channels designated “a” through“d” comprising bipolar leads with ring electrodes 34 a-d and tipelectrodes 33 a-d, sensing amplifiers 31 a-d, pulse generators 32 a-d,and channel interfaces 30 a-d. Each channel thus includes a pacingchannel made up of the pulse generator connected to the electrode and asensing channel made up of the sense amplifier connected to theelectrode. By appropriate placement of the electrode, a channel may beconfigured to sense and/or pace a particular atrial or ventricular site.The channel interfaces 30 a-d communicate bidirectionally withmicroprocessor 10, and each interface may include analog-to-digitalconverters for digitizing sensing signal inputs from the sensingamplifiers and registers that can be written to by the microprocessor inorder to output pacing pulses, change the pacing pulse amplitude, andadjust the gain and threshold values for the sensing amplifiers. Thesensing circuitry of the pacemaker detects a chamber sense, either anatrial sense or ventricular sense, when an electrogram signal (i.e., avoltage sensed by an electrode representing cardiac electrical activity)generated by a particular channel exceeds a specified detectionthreshold. Pacing algorithms used in particular pacing modes employ suchsenses to trigger or inhibit pacing, and the intrinsic atrial and/orventricular rates can be detected by measuring the time intervalsbetween atrial and ventricular senses, respectively.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a MOS switching network 70 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing or can 60 serving as a ground electrode. As explainedbelow, one way in which the device may alter the spatial distribution ofpacing is to switch from unipolar to bipolar pacing (or vice-versa) orto interchange which electrodes of a bipolar lead are the cathode andanode during bipolar pacing. A shock pulse generator 50 is alsointerfaced to the controller for delivering a defibrillation shock via apair of shock electrodes 51 to the atria or ventricles upon detection ofa shockable tachyarrhythmia.

The controller controls the overall operation of the device inaccordance with programmed instructions stored in memory, includingcontrolling the delivery of paces via the pacing channels, interpretingsense signals received from the sensing channels, and implementingtimers for defining escape intervals and sensory refractory periods. Anexertion level sensor 330 (e.g., an accelerometer, a minute ventilationsensor, or other sensor that measures a parameter related to metabolicdemand) enables the controller to adapt the pacing rate in accordancewith changes in the patient's physical activity. A telemetry interface40 is also provided which enables the controller to communicate with anexternal device 300 such as an external programmer via a wirelesstelemetry link. An external programmer is a computerized device with anassociated display and input means that can interrogate the pacemakerand receive stored data as well as directly adjust the operatingparameters of the pacemaker. The external device 300 shown in the figuremay also be a remote monitoring unit. The external device 300 may alsobe interfaced to a patient management network 91 enabling theimplantable device to transmit data and alarm messages to clinicalpersonnel over the network as well as be programmed remotely. Thenetwork connection between the external device 300 and the patientmanagement network 91 may be implemented by, for example, an internetconnection, over a phone line, or via a cellular wireless link.

The controller is capable of operating the device in a number ofprogrammed pacing modes which define how pulses are output in responseto sensed events and expiration of time intervals. Most pacemakers fortreating bradycardia are programmed to operate synchronously in aso-called demand mode where sensed cardiac events occurring within adefined interval either trigger or inhibit a pacing pulse. Inhibiteddemand pacing modes utilize escape intervals to control pacing inaccordance with sensed intrinsic activity such that a pacing pulse isdelivered to a heart chamber during a cardiac cycle only afterexpiration of a defined escape interval during which no intrinsic beatby the chamber is detected. Escape intervals for ventricular pacing canbe restarted by ventricular or atrial events, the latter allowing thepacing to track intrinsic atrial beats. Multiple excitatory stimulationpulses can be delivered to multiple sites during a cardiac cycle inorder to both pace the heart in accordance with a bradycardia mode andprovide additional excitation to selected sites.

3. Delivery of Intermittent Stress Augmentation Pacing

The device shown in FIG. 1 can be configured to deliver intermittentstress augmentation pacing in a number of different ways. In oneembodiment, which may be suitable for patients who need neitherbradycardia nor resynchronization pacing, the device is programmed todeliver no pacing therapy at all except at periodic intervals (e.g., forfive minutes each day). The pacing therapy may then be delivered in anyselected pacing mode such as right ventricle-only, left ventricle-only,or biventricular pacing. In certain patients who are implanted with apacemaker, intermittent pacing may occur fortuitously if the patient isrelatively chronotropically competent and without AV block and if theprogrammed escape intervals of the pacemaker are long enough. In orderto reliably provide augmented stress pacing and a cardioprotectiveeffect, however, the pacemaker should be programmed so that the pacingis delivered irrespective of the patient's intrinsic rate at scheduledintervals. Other embodiments, which may be suitable for patients whoneed bradycardia and/or resynchronization pacing, deliver intermittentstress augmentation pacing by intermittently varying the spatialdistribution of the pacing pulses applied by intermittently switchingfrom a normal operating mode to one or more stress augmentation pacingmodes. Switching to a stress augmentation mode may include altering thedevice's pacing pulse output configuration and/or pulse output sequencein order to initially excite different myocardial regions and therebycause later excitation of different regions distal to the pacing site orsites, where the pulse output configuration specifies a specific subsetof the available electrodes to be used for delivering pacing pulses andthe pulse output sequence specifies the timing relations between thepulses. The pulse output configuration is defined by the controllerselecting particular pacing channels for use in outputting pacing pulsesand by selecting particular electrodes for use by the channel withswitch matrix 70. If the normal operating mode is a primary pacing modefor delivering ventricular pacing therapy, the stress augmentation modemay then excite the ventricular myocardium at a site or sites differentfrom the primary pacing mode in order to vary the spatial pattern ofdepolarization and cause a particular myocardial region to experienceincreased mechanical stress. Intermittent spatial variation in pacingmay be produced, for example, by intermittently switching from a leftventricle-only pacing mode to a right ventricle-only pacing mode orvice-versa, intermittently witching from a biventricular or othermultiple ventricular pacing mode to a single ventricle pacing mode orvice-versa. Spatial variation in pacing may also be produced byemploying a bipolar pacing lead with electrodes spaced relatively farapart and then intermittently switching from unipolar to bipolar pacingor vice-versa, or intermittently interchanging which electrodes of thebipolar lead are the cathode and anode during bipolar pacing.

By the use of multiple pacing electrodes located at different pacingsites, a number of stress augmentation modes may be intermittentlyswitched to in order to provide augmented stress to multiple myocardialregions. Each such stress augmentation mode may be defined by a certainpulse output configuration and pulse output sequence, and delivery ofintermittent stress augmentation may involve temporarily switching toeach mode according to a programmed schedule, where the device remainsin the stress augmentation mode for a specified time period, referred toas the stress augmentation period (e.g., 5 minutes). By appropriateplacement of the pacing electrodes, a cardioprotective effect may beprovided to a large area of the ventricular myocardium. Such multiplepacing sites may be provided by multiple leads or by leads havingmultiple electrodes incorporated therein. For example, amultiple-electrode lead may be threaded into the coronary sinus in orderto provide multiple left ventricular pacing sites. In one embodiment,stress augmentation pacing is delivered during each cardiac cycle asmulti-site pacing through a plurality of the multiple electrodes. Inanother embodiment, the stress augmentation pacing is delivered assingle-site pacing where the pacing site may be alternated between themultiple electrodes during successive cardiac cycles or during differentstress augmentation periods. A switch to a stress augmentation mode mayalso include adjusting one or more pacing parameters such as the escapeintervals that determine pacing rate in order to ensure that the stressaugmentation paces are not inhibited by intrinsic cardiac activity.

As described above, the device controller may be programmed tointermittently switching from a normal operating mode to a stressaugmentation mode. In the normal operating mode, the device may eitherdeliver no therapy at all or may deliver a pacing therapy in a primarypacing mode with a different pacing configuration, a different pulseoutput sequence, and/or different pacing parameter settings from that ofthe stress augmentation mode. The device may be equipped with a singleventricular pacing channel or with multiple ventricular pacing channelseach having a pacing electrode disposed at a different pacing site. Inone example, the stress augmentation mode then uses at least one pacingchannel not used in the primary pacing mode. The device initiates stressaugmentation pacing upon receiving a command to switch to the stressaugmentation mode for a specified period of time, where such a commandmay be generated internally according to a defined schedule and/ortriggering condition detected by the implantable device, received froman external programmer, or received via a patient management network.

Once a command to switch to the stress augmentation mode is received,the device may then simply switch to the stress augmentation mode for aspecified period of time where the pacing parameters are predefinedvalues. For example, the stress augmentation pacing may be delivered tothe ventricles in an atrial triggered synchronous mode (e.g., DDD orVDD) with predefined atrio-ventricular (AV) and ventricular-ventricular(VV) escape intervals or in a non-atrial triggered ventricular pacingmode (e.g., VVI) with a pre-defined VV escape interval where the lengthof the escape intervals may be set to values which result in a highpacing frequency. It may be desirable, however, to incorporateadditional steps into the algorithm before switching. For example, theescape intervals for the stress augmentation mode may be dynamicallydetermined before the mode switch in order to ensure a high pacingfrequency. In an embodiment where the stress augmentation mode is anon-atrial triggered pacing mode, the device may measure the patient'sintrinsic heart rate before the mode switch and then set the VV escapeinterval so that the pacing rate for the stress augmentation mode isslightly higher than the intrinsic rate. If the patient is receivingrate-adaptive ventricular pacing therapy in the primary pacing mode, theVV escape interval for the stress augmentation mode may be similarlymodulated by an exertion level measurement. In an embodiment where thestress augmentation pacing is delivered in an atrial triggered pacingmode, the device may measure the patient's intrinsic AV interval beforethe mode switch (e.g., as an average over a number of cycles precedingthe mode switch) so that the AV escape interval for deliveringventricular pacing in an atrial triggered mode can be set to pace theventricles at a high frequency during the stress augmentation period.

It may also be desirable in certain patients for the device to check thepatient's exertion level before switching to the stress augmentationmode and cancel the mode switch if the exertion level is above a certainthreshold. This may be the case if the patient's ventricular function issomewhat compromised by the stress augmentation pacing. Alternatively,the device could be programmed to use a specified minimum measuredexertion level as a triggering condition to initiate the stressaugmentation mode, where the stress augmentation mode is then maintainedfor some specified period of time and/or until the measured exertionlevel rises above a specified value. Conversely, for certain patients,it may be desirable to deliver stress augmentation pacing when thepatient's exertion level is higher than some specified value. Forexample, the measured exertion level (e.g., either minute ventilation oractivity level as measured by an accelerometer) can be used either aloneor in conjunction with the time of day (as determined by themicroprocessor with its internal clock) to provide an indication thatthe patient is either awake or sleeping. Depending on the patient, thedevice may then be programmed to deliver stress augmentation pacing onlyif the patient is expected to be awake or expected to be sleeping.

FIG. 2 illustrates an exemplary algorithm for delivering stressaugmentation pacing. At step A1, the device waits for a command toswitch to the stress augmentation mode. Upon receiving the command, thepresent exertion level is checked against a specified limit value atstep A2. If the exertion level is below the limit value, the device nextsets the AV delay and VV escape intervals for stress augmentation pacingin an atrial triggered pacing mode at step A3, where the escapeintervals are set in accordance with the patient's currently measuredheart rate or intrinsic AV interval. At step A4, the device thenswitches to the stress augmentation mode for a specified period of time.

Stress augmentation pacing as described above may be delivered inconjunction with other therapies for treating cardiac disease such asresynchronization pacing, neurostimulation, drug delivery, and gene orother biological therapy. Accordingly, an implantable device such asdescribed above may also be configured with the capability of deliveringone or more of those additional therapies. Examples of devices fordelivering such therapies, and which may be additionally configured todeliver stress augmentation pacing as described herein, may be found inco-pending and commonly assigned U.S. patent application Ser. Nos.10/850,341, 11/078,460, 11/063,170, 11/075,838, 11/125,503, and11/088,231, the disclosures of which are hereby incorporated byreference in their entirety. Such additional therapies may be deliveredas part of the stress augmentation mode or according to separateschedules and/or triggering conditions.

4. Ischemia Detection

Stress augmentation pacing, as described above, exerts itscardioprotective effect by subjecting particular regions of themyocardium to increased mechanical stress for brief periods of time ascompared with the stress otherwise experienced by those regions ineither a primary pacing mode or during normal intrinsic contractions.Although it is believed that stress augmentation pacing does not causeischemia in the stressed regions under normal conditions, it maynonetheless be desirable to inhibit a switch to a stress augmentationmode if the patient is presently experiencing some degree of cardiacischemia. Accordingly, the device may be configured to detect cardiacischemia from a morphology analysis of an electrogram collected duringan intrinsic or a paced beat, the latter sometimes referred to as anevoked response. The electrogram for detection of ischemia is recordedfrom a sensing channel that senses the depolarization and repolarizationof the myocardium during a cardiac cycle. The sensing channel used forthis purpose may be a sensing channel used for detecting cardiacarrhythmias and/or intrinsic beats or may be a dedicated channel. Inorder to detect ischemic changes in an electrogram, it may be preferableto record the electrogram with a unipolar electrode that “sees” a largervolume of the myocardium as a wave of electrical activity spreads than abipolar electrode. In order to detect an ischemic change, theelectrogram can be compared with a reference electrogram to see if anincreased current of injury is present. The comparison may involve, forexample, cross-correlating the recorded and reference electrograms orcomparing ST segment amplitudes, slopes, or integrations with referencevalues.

In order to detect whether the patient is experiencing cardiac ischemiaduring pacing, the controller is programmed to analyze the recordedelectrogram of an evoked response and look for a “current of injury.”When the blood supply to a region of the myocardium is compromised, thesupply of oxygen and other nutrients can become inadequate for enablingthe metabolic processes of the cardiac muscle cells to maintain theirnormal polarized state. An ischemic region of the heart thereforebecomes abnormally depolarized during at least part of the cardiac cycleand causes a current to flow between the ischemic region and thenormally polarized regions of the heart, referred to as a current ofinjury. A current of injury may be produced by an infarcted region thatbecomes permanently depolarized or by an ischemic region that remainsabnormally depolarized during all or part of the cardiac cycle. Acurrent of injury results in an abnormal change in the electricalpotentials measured by either a surface electrocardiogram or anintracardiac electrogram. If the abnormal depolarization in theventricles lasts for the entire cardiac cycle, a zero potential ismeasured only when the rest of the ventricular myocardium hasdepolarized, which corresponds to the time between the end of the QRScomplex and the T wave in an electrogram and is referred to as the STsegment. After repolarization of the ventricles, marked by the T wave inan electrogram, the measured potential is influenced by the current ofinjury and becomes shifted, either positively or negatively dependingupon the location of the ischemic or infarcted region, relative to theST segment. Traditionally, however, it is the ST segment that isregarded as shifted when an abnormal current of injury is detected by anelectrogram or electrocardiogram. A current injury produced by anischemic region that does not last for the entire cardiac cycle may onlyshift part of the ST segment, resulting in an abnormal slope of thesegment. A current of injury may also be produced when ischemia causes aprolonged depolarization in a ventricular region which results in anabnormal T wave as the direction of the wave of repolarization isaltered.

In order to detect a change in an electrogram indicative of ischemia, arecorded electrogram is analyzed and compared with a referenceelectrogram, which may either be a complete recorded electrogram orparticular reference values representative of an electrogram. Becausecertain patients may always exhibit a current of injury in anelectrogram (e.g., due to CAD or as a result of electrode implantation),the controller is programmed to detect ischemia by looking for anincreased current of injury in the recorded electrogram as compared withthe reference electrogram, where the latter may or may not exhibit acurrent of injury. FIG. 3 shows examples of evoked response data for twocases labeled A and B, where A is the baseline reference and B is duringan acute ischemic episode. A surface electrocardiogram labeled ECG, apacing timing diagram labeled PTD, and an electrogram labeled ER areillustrated for each case. The ST segment of the electrogram for case Bis seen to have different amplitudes and slopes as compared with theamplitudes and slopes of the ST segment of the electrogram for case A.One way to look for an increased current of injury in the recordedelectrogram is to compare the ST segment amplitude and/or slope with theamplitude and slope of a reference electrogram. Various digital signalprocessing techniques may be employed for the analysis, such as usingfirst and second derivatives to identify the start and end of an STsegment. Other ways of looking for a current injury may involve, forexample, cross-correlating the recorded and reference electrograms toascertain their degree of similarity. The electrogram could beimplicitly recorded in that case by passing the electrogram signalthrough a matched filter that cross-correlates the signal with areference electrogram. The ST segment could also be integrated, with theresult of the integration compared with a reference value to determineif an increased current of injury is present.

If a change in a recorded electrogram indicative of ischemia isdetected, the controller may be programmed to inhibit switching to astress augmentation pacing mode. Detection of cardiac ischemia may alsobe logged as a clinically significant event in the pacemaker's memory,where the event log and/or the recorded electrogram exhibiting theischemia may then be later downloaded to a clinician for analysis via anexternal programmer. Information derived from other analyses or othersensing modalities may also be used to more specifically detect cardiacischemia. For example, dyspnea or other abnormal breathing patterns maybe detected using a minute ventilation sensor by programming thecontroller to compare the transthoracic impedance signal from the sensorwith a template representing the abnormal pattern.

5. Specific Applications

Stress augmentation pacing as described above may be applied to anypatient with cardiac disease who would benefit from a stress inducedcardioprotective effect. As noted above, it is believed that theincreased myocardial stress brought about by stress augmentation pacingpreconditions the heart through a signal transduction cascade whichcauses the release of certain cellular constituents and/or inducesexpression of particular genes. Such preconditioning allows the heart tobetter withstand the effects of cardiac ischemia. Activation of thesesame cellular pathways via stress augmentation pacing can also preventor reverse the cardiac remodeling caused, for example, by pressure orvolume overload. Stress augmentation pacing can therefore be applied tobenefit patients who either have or are likely to develop heart failure,whether or not ischemic cardiac disease is also present. As heartfailure is often due to or exists concomitantly with ischemic cardiacdisease, these separate benefits of stress augmentation pacing will worktogether in most situations.

Although the invention has been described in conjunction with theforegoing specific embodiments, many alternatives, variations, andmodifications will be apparent to those of ordinary skill in the art.Other such alternatives, variations, and modifications are intended tofall within the scope of the following appended claims.

1. A method, comprising: implanting a device that includes a pacingchannel for delivering pacing pulses to a selected myocardial site and acontroller for controlling the delivery of pacing pulses in accordancewith a programmed pacing mode; and, programming the controller tointermittently switch from a normal operating mode to a stressaugmentation mode in which a particular region or regions of themyocardium are subjected to increased mechanical stress as compared withthe stress experienced by those regions during the normal operatingmode.
 2. The method of claim 1 wherein the normal operating mode is aprimary pacing mode for delivering pacing therapy and wherein stressaugmentation mode causes a different depolarization pattern than theprimary pacing mode.
 3. The method of claim 2 wherein the stressaugmentation mode excites the myocardium at a site or sites differentfrom the primary pacing mode.
 4. The method of claim 2 wherein theswitch from a primary pacing mode to a stress augmentation mode involvesswitching form bipolar pacing to unipolar pacing or vice-versa.
 5. Themethod of claim 2 wherein the switch from a primary pacing mode to astress augmentation mode involves switching which electrode of a bipolarpacing lead is the cathode and which electrode is the anode.
 6. Themethod of claim 2 wherein the implanted device that includes multiplepacing channels for delivering pacing pulses to a plurality of pacingsites, and further comprising programming the controller such that thestress augmentation mode uses at least one pacing channel not used inthe primary pacing mode.
 7. The method of claim 6 wherein the switchfrom a primary pacing mode to a stress augmentation mode involvesswitching from left ventricle-only pacing to right ventricular pacing orvice-versa.
 8. The method of claim 6 wherein the switch from a primarypacing mode to a stress augmentation mode involves switching frombiventricular pacing to single ventricular pacing or vice-versa.
 9. Themethod of claim 1 wherein the implanted device includes an exertionlevel sensor and further comprising programming the controller such thatthe switch from a normal operating mode to a stress augmentation mode isinhibited if the measured exertion level is above a specified limitvalue.
 10. The method of claim 1 further comprising programming thecontroller to detect cardiac ischemia from an electrogram morphologyanalysis and such that the switch from a normal operating mode to astress augmentation mode is inhibited if cardiac ischemia is detected.11. The method of claim 1 wherein the device is implanted into a patientwho has or is likely to develop heart failure.
 12. The method of claim 1wherein the device is implanted into a patient who has or is likely todevelop cardiac ischemia.
 13. The method of claim 1 further comprisingprogramming the controller to switch to the stress augmentation modeaccording to a defined schedule.
 14. The method of claim 1 furthercomprising programming the controller to switch to the stressaugmentation mode upon receiving a command to do so via a patientmanagement network.
 15. The method of claim 1 further comprisingprogramming the controller to switch to the stress augmentation modewhen a measured exertion level is above a specified value.
 16. Themethod of claim 1 further comprising programming the controller toswitch to the stress augmentation mode when a measured exertion level isbelow a specified value.
 17. The method of claim 1 further comprisingprogramming the controller to switch to the stress augmentation modewhen a measured exertion level is below a specified value and adetermined time of day indicates the patient is expected to be sleeping.18. The method of claim 1 further comprising programming the controllerto switch to the stress augmentation mode when a measured exertion levelis above a specified value and a determined time of day indicates thepatient is expected to be awake.